A complete understanding of the cellular and molecular basis of the anesthetized state produced by volatile anesthestics remains elusive. Ion channel proteins provide the most likely molecular targets for these agents. Many studies have provided evidence for the involvement of GABAergic and glutamatergic receptor systems in mediating the action of volatile anesthetics. An additional type of ionic current, background potassium currents(also known as resting or baseline K+ currents) have recently been identified as plausible sites for volatile anesthetic action. This grant is a continuation of studies begun six years ago to elucidate the role of background K+ currents in normal physiology and in the anesthetized state. A new structural class of K+ channels with two pore-forming sequences in tandem are responsible for background K+ currents. We have cloned members of this family, demonstrated their presence in the central nervous system and studied their activation by volatile anesthetics at concentrations overlapping the clinical range. Other investigators have recorded the activity of background K+ channels in vivo and demonstrated inhibitory effects on neuronal systems that are enhanced by volatile anesthetics. The aims of this grant are threefold: (1) to characterize the function and anesthetic sensitivity of the remaining undiscovered members of this structural class of ion channels; (2) to study at the cellular level the tissue distribution of tandem pore K+ channels to gain insight into their normal physiologic function; (3) to identify the molecular domains responsible for volatile anesthetic action. With these experiments we expect that a more complete understanding of background K+ channels will emerge and their role in mediating the anesthetic state clarified.